Process for the preparation of latanoprost

ABSTRACT

Disclosed is a novel process for the preparation of the anti-glaucoma drug Latanoprost, in good yield, in large amounts and with desired purity. Also disclosed are novel intermediates for the above process.

FIELD OF THE INVENTION

[0001] This invention relates to a novel process for the preparation of13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂ _(α) isopropyl ester(Latanoprost) of the formula [1]:

[0002] drug for treating glaucoma (Merck Index, 12th Ed., 5787).

BACKGROUND OF THE INVENTION

[0003] The known methods for synthesis of Latanoprost (see B. Resul etal., J. Med. Chem., 1993, 36, 243) include the stage of reducing oflactone-group of the compound [20] with excess of diisobutylaluminumhydride (DIBAL-H) at −72-−80° C. to give the compound [11b] (Scheme 1):

[0004] However, this method is problematic as it is difficult toscale-up this highly exothermic reaction at such low temperatureconditions. Furthermore, it was feared that increasing of temperatureduring DIBAL-H addition may lead to undesired processes in reduction ofproduct [11b].

OBJECTS OF THE INVENTION

[0005] It is an object of this invention to provide a novel process forthe preparation of Latanoprost in good yield, in large amounts and withdesired purity.

[0006] It is a further object of this invention to provide novelintermediates for the above process.

SUMMARY OF THE INVENTION

[0007] The above objects are achieved by present invention, whichprovides a process for the preparation of Latanoprost [1]

[0008] which comprises deriving the compound [5]

[0009] to give the compound [7]

[0010] which is hydrogenated in the presence of catalyst to give thecompound of the Formula [9]

[0011] which is reduced with diisobutylaluminum hydride at temperaturerange from −50 to +50° C. followed by hydrolysis of the obtainedreaction mixture under basic conditions to give compound [11], which isconverted into latanoprost [1]

[0012] werein one of R¹ and R² is an aryl carbonyl and the other one isselected from the group consisting of aryl carbonyl, acyl,trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted andalkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-ylgroups;

[0013] R³ is hydrogen when R¹ is acyl and is equal to R¹ when it istrialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted oralkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-ylgroups; and

[0014] R⁴ is hydrogen when R² is acyl and is equal to R² when it istrialkylsiyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted oralkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-ylgroups.

[0015] Some of the new compounds [7] and [9] which are obtained asintermediates in the process of the present invention may be purified bycrystallization from organic solvents. This fact represent a furtheraspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0016] An advantage of the present invention is the fact that the highlyselective reduction of lactone-group of the compound [9] withdiisobutylaluminum hydride may proceed at industrially acceptabletemperature range from −50 to +50° C., preferably from −20 to +20° C. Onthe basis of this we developed a new effective process for synthesis ofLatanoprost [1] which process comprises the steps of:

[0017] a) stereoselective reduction of oxo-group of compound of theFormula [4]:

[0018] wherein R¹ is defined as above,

[0019] to yield a mixture of compounds of the Formula [5] (main product)and [6] (minor product):

[0020] wherein R¹ is defined as above;

[0021] b) separating the desired compound [5] from the by-product [6] bycolumn chromatography followed by oxidation of the hydroxy-group of thecompound [6] for regeneration of compound [4].

[0022] c) deriving compound [5] to give compound [7]:

[0023] wherein R¹ and R² are as defined above;

[0024] d) hydrogenating compound [7] in the presence of a catalyst toyield compound [9]:

[0025] wherein R¹ and R² are as defined above;

[0026] e) reducing compound [9] with diisobutylaluminum hydride attemperature −50 to +50° C. followed by hydrolysis of the obtainedreaction mixture under basic conditions to give compound [11]:

[0027] wherein R³ and R⁴ are as defined above;

[0028] f) reacting compound [11] with metal salt of5-(triphenylphosphoranylidene)pentanoic acid to obtain compound [13]:

[0029] wherein R³ and R⁴ are as defined above;

[0030] g) esterifying compound [13] with compound [16]:

(CH₃)₂CHX  [16]

[0031] wherein X is a leaving group, in the presence of base to obtainthe compound of the Formula [17]:

[0032] wherein R³ and R⁴ are as defined above; and,

[0033] h) when one of R³ or R⁴ in compound [17] is other than hydrogenremoving the protecting group to yield Latanoprost [1].

[0034] The described process of Latanoprost [1] production may besummarized by the following Scheme 2.

[0035] If one of R³ or R⁴ is other than hydrogen, Latanoprost [1] mayalternatively be prepared from the compound [11] through Latanoprostacid [13b] according to Scheme 3:

[0036] Alternatively, compound [9] may be prepared reducing of compound[5] followed by deriving obtained compound [21] to give compound [9](Scheme 4):

[0037] An alternative approach to prepare compound [7] may involvederiving the mixture of the compounds [5] and [6], formed after reducingof the ketone [4], to give a mixture of the compounds [7] and [8],separating the compound [7] from the by-product [8] by columnchromatography and/or fractional crystallization, removing R²-protectinggroup from the compound [8] to give the compound [6] following oxidizingthe hydroxy-group of the compound [6] for regeneration of the compound[4] (Scheme 5):

[0038] Preferably the R¹ and R² are selected from the group consistingof benzoyl, p-toluoyl, p-phenylbenzoyl and tetrahydro-2H-pyran-2-ylgroups.

[0039] Preferably the stereoselective reduction of the compound [4] iscarried out with (−)-B-chlorodiisopinocamphenylborane or with borane inthe presence of 2-alkyl-CBS-oxazaborolydines. More preferably the saidreduction is carried out with (−)-B-chlorodiisopinocamphenylborane inorganic solvent. Preferably the said organic solvent is tetrahydrofuran,ether, 1,2-dimethoxyethane, toluene, hexane, dichloromethane or mixturethereof.

[0040] Preferably the catalyst for hydrogenation of compound [7] tocompound [9] must contain palladium, platinum or nickel. More preferablythe catalyst is palladium-on-carbon, platinum oxide orplatinum-on-carbon. Preferably the said hydrogenation is provided in thepresence of solvents and bases or salts. Preferably the said bases areselected from the group consisting tertiary and secondary amines.Preferably the said salts are selected from the group consisting ofmetal nitrites, metal alkanoates and metal benzoates.

[0041] It is important in the process of the present invention that somenew compounds [7] and [9] may be purified by crystallization fromorganic solvents.

[0042] If reduction of compound [9] is carried out with not more than 2equivalents of diisobutylaluminum hydride (DIBAL-H), intermediate [10]may be isolated from the reaction mixture. Basic hydrolysis of thecompound [10] gives the compound [11]. It should be noted that usingexcess of diisobutylaluminum hydride (DIBAL-H) for reduction of compound[9] to compound [11] at −50-+50° C. is complicated by further reductionto by-product [12]:

[0043] wherein R¹, R², R³and R⁴are as defined above.

[0044] To increase the yield of [11] it is desirable to add DIBAL-H tocompound [9] at −50-+50° C. (preferably at −20-+20° C.) to reach notmore than 93-99% conversion of lactone-groups. Preferably, this reactionis conducted in the presence of an organic solvent. Preferably, theorganic solvent is toluene, tetrahydrofuran, ether, dichloromethane ormixture thereof. Preferably, the following basic hydrolysis is conductedwith organic bases or metal hydroxides or carbonates in a solventpossibly in the presence of phase transfer catalyst. Preferably themetal is alkali or alkaline-earth metal and the solvent is a neutralorganic solvent, C₁₋₄ alkanol or water or mixture thereof. Process ofreduction of the compound [9] with diisobutylaluminum hydride may bepresented by Scheme 6:

[0045] It is desired to purify the compound [13] by columnchromatography or/and crystallization its salt with amine from a solventfollowing isolation of purified compound [13] from the salt. Preferablythe said amine is tromethamine, histamine, L-arginine, triptamine oradamantanamine.

[0046] Preferably the esterifying of the compound [13] is provided withisopropyl iodide, bromide, methanesulfonate, p-toluenesulfonate,p-nitrophenylsulfonate, 2,4-dinitrophenylsulfonate or triflate in thepresence of organic solvent and organic or inorganic base. Preferablythe said organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N,N-diisopropylethylamine or diisopropylamine. Preferably the saidinorganic base is alkali or alkaline-earth metal carbonate or hydroxide.Most preferably, the said inorganic base is potassium or cesiumcarbonate. Preferably the said solvent is acetone, methyl ethyl ketone,THF, DMF, dichloromethane, ethanol, isopropanol or acetonitrile.

[0047] The compound [4] may be prepared from the commercially availablecompounds [2a-c] according to Scheme 7:

[0048] This invention will be better understood from the Examples thatfollows. However, the examples illustrate, but do not limit, theinvention. Those skilled in the art will readily appreciate that thespecific methods and results discussed are merely illustrative of theinvention as described more fully in the claims that follow thereafter.

EXAMPLE 1

[0049]

1) Preparation of dimethyl (2-oxo-4-phenylbutyl)phosphonate 1.1)1-Bromo-4-phenyl-2-butanone

[0050] A freshly prepared solution of bromine (258.9 g) in methanol (600mL) was added dropwise during 1 h 20 min to a stirred solution ofbenzylacetone (222.3 g) in methanol (600 mL) at 7-10° C. An exothermicreaction took place, and to maintain the necessary temperature (7-10°C.), the flask should be immersed in a ice-water bath. When orange-redcolor of bromine disappeared, water (1500 mL) was added to the mixtureand the obtained mixture was stirred overnight. The organic layer (onthe bottom) was separated, water phase was extracted withdichloromethane (2×600 mL). The combined organic layers were dried oversodium sulfate, filtered and evaporated under reduced pressure. The oilyresidue was dissolved in hexane (2500 mL) and the obtained solution waskept overnight at −10° C. Precipitated fine crystals (needles) werefiltered off, washed on filter with cold hexane, dried under reducedpressure at room temperature to give 1-bromo-4-phenyl-2-butanone (213.0g, 63% yield), mp 39-40° C. ¹H NMR (CDCl₃) δ2.95-3.00 (m, 4H); 3.83 (s,2H); 7.16-7.30 (m, 5H).

1.2) 1-Iodo-4-phenyl-2-butanone

[0051] A solution of 1-bromo-4-phenyl-2-butanone (18.9 g) in dry acetone(100 mL) was added dropwise to a stirred solution of sodium iodide (14.0g) in dry acetone (100 mL) at room temperature. A precipitate of sodiumbromide immediately formed. The mixture was stirred overnight at roomtemperature, filtered and evaporated under reduced pressure. The residuewas dissolved in dichloromethane (150 mL). The solution was washed withwater, dried over sodium sulfate and evaporated under reduced pressure.The oily residue was dissolved in 95% ethanol (100 mL). The obtainedsolution was kept at −10° C. overnight. Precipitated pale yellow needleswere filtered off, dried under reduced pressure at room temperature toobtain 20.0 g (88% yield) of 1-iodo-4-phenyl-2-butanone, mp 44-45° C. ¹HNMR (CDCl₃) δ: 2.88-3.07 (m, 4H); 3.75 (s, 2H); 7.16-7.31 (m, 5H).

1.3) Dimethyl (2-oxo-4-phenylbutyl)phosphonate

[0052] A 0.5 L four necked flask equipped with condenser connected tobubbler, thermometer, dropping funnel with pressure equalization arm anddeep-tube for bubbling argon through the reaction mixture was chargedwith a solution of 1-iodo-4-phenyl-2-butanone (89.5 g) in acetonitrile(250 mL). Trimethylphosphite (80.9 g) was added dropwise to thesolution, over 1.5 h, with simultaneous bubbling of an argon through thereaction mixture. The temperature of the reaction mixture was allowed tochange from 23° C. to 43° C. The resulting mixture was refluxed during 1h and evaporated under reduced pressure. The residue was fractionallydistilled at 0.05 mm Hg to give 71.0 g (85% yield) of dimethyl(2-oxo-4-phenylbutyl)phosphonate, bp 129-130° C./0.05 mm Hg. ¹H NMR(CDCl₃, δ) 2.88-2.92 (m, 4H); 2.98 (t, J=23 Hz; 2H); 3.68 (s, 3H); 3.74(s, 3H); 7.14-7.24 (m, 5H).

2) Preparation of(3aR,4R,5R,6aS)-4-formylhexahydro-5-(p-phenylbenzoyloxy)-2H-cyclopenta[b]furan-2-one[3a]

[0053] Corey lactone [2a] (80.7 g) was added by portions to a stirredsuspension of Dess-Martine reagent (116.6 g) in dichloromethane (700 mL)at 0-3° C. (ice/water bath). The mixture was stirred for 40 min(temperature rose to 14° C.) until lactone [2a] spot disappeared in TLCmonitoring. The resulting mixture poured into a solution of sodiumbicarbonate (130 g) and sodium thiosulfate pentahydrate (350 g) in water(1.5 L). The mixture was stirred for about 10 min. The organic layer wasseparated and the water layer was extracted with dichloromethane (2×350mL). The combined organic solutions were washed with saturated solutionof sodium bicarbonate, dried over sodium sulfate, filtered andimmediately introduced into the following step.

3) Preparation of(3aR,4R,5R,6aS)-hexahydro-4-(3-oxo-5-phenyl-1E-pentenyl)-5-(p-phenylbenzoyloxy)-2H-cyclopenta[b]furan-2-one[4a]

[0054] A solution of dimethyl (2-oxo-4-phenylbutyl)phosphonate (69.1 g)in dichloromethane (200 mL) was added dropwise at 0° C. to a suspensionof sodium hydride (11.9 g) in dichloromethane (700 mL). The mixture wasstirred at 0° C. during 1 h. The cold (0-5° C.) solution of aldehyde[3a] in dichloromethane prepared in the previous stage was addeddropwise to the stirred mixture at 0-5° C. The obtained mixture wasstirred for 1 hour at the same temperature (TLC monitoring), filteredthrough Celite and acidified with acetic acid to pH 5 at 0-5° C. Theorganic layer was separated, washed with water until the pH of the waterlayer was not less than 6.8, dried over sodium sulfate, filtered andevaporated under reduced pressure. The oily residue was triturated withether (500 mL). The precipitated crystals were filtered and dried underreduced pressure to a constant weight to give 93.4 g (85% yield) ofcrude crystalline product. A solution of the product in acetonitrile waspassed through Celite and evaporated under reduced pressure Thecrystalline residue was recrystallizated from methanol (2 L) gave 83.6 g(76.2% yield) of compound [4a] with mp 134-135° C. and [α]_(D) ²⁰-141.7°(c 1.26, MeCN). ¹H NMR (CDCl₃, δ) 2.32-2.63 (m, 3H); 2.84-2.97 (m, 7H);5.00-5.10 (m, 1H); 5.20-5.35 (m, 1H); 6.20 (d, J=16 Hz, 1H); 6.65 (dd,J=16 and 8 Hz, 1H); 7.15-7.67 (m, 12H); 8.03 (d, J=8 Hz, 2H).

EXAMPLE 2(3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3S)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]-1E-pentenyl]-2H-cyclopenta[b]furan-2-one[7a]

[0055]

1) Preparation of (3aR,4R,5R,6aS)-hexahydro-4-[(3S) and(3R)-3-hydroxy-5-phenyl-1E-pentenyl]-5-(p-phenylbenzoyloxy)-2H-cyclopenta[b]furan-2-ones[5a] and [6a]

[0056] A solution of (−)-B-chlorodiisopinocamphenylborane (26.0 g) inTHF (150 mL) was added dropwise at −23-−25° C. to a stirred solution ofthe compound [4a] (26.0 g) in THF (250 mL). The mixture was stirred atthis temperature during 8 h (TLC monitoring) and then quenched by adding30 mL of Methanol at −23-−25° C. The resulting solution was allowed towarm to room temperature and was stirred at this temperature for 14 h.The mixture was concentrated to a volume 70-100 mL and dichloromethane(400 mL) and water (200 mL) were added to it. The organic layer wasseparated, water layer was extracted with dichloromethane (3×100 mL).The combined organic layers were washed with a 25 wt. % aq. solution ofammonium chloride (2×80 g), dried over sodium sulfate, filtered andevaporated under reduced pressure. The residue ([5a]/[6a] 95:5 by HPLC)was triturated with hexane (150 mL) and the obtained solid was filteredoff. This solid with methanol (20 mL) and isopropyl ether (130 mL) wasrefluxed during 30 min and cooled to room temperature. The precipitatedsolid was filtered off and dried under reduced pressure to give 22.0 g(85% yield) of a mixture of compounds [5a] and [6a], where [5a]/[6a] is96:4 by HPLC.

2) Preparation of(3aR,4R,5R,6aS)-hexahydro-5-(p-phenylbenzoyloxy)-4-[(3S)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]-1E-pentenyl]-2H-cyclopenta[b]furan-2-one[7a] and its (3R)-isomer [8a]

[0057] Pyridinium p-toluenesulfonate (0.2 g) was added to a stirredsolution of diastereomeric alcohols [5a] and [6a] (23.8 g, [5a]/[6a]96:4 by HPLC), and 3,4-Dihydro-2H-pyran (15.7 g) in dichloromethane (250mL) at room temperature. The mixture was stirred overnight at roomtemperature (TLC monitoring), washed with saturated aqueous solution ofsodium bicarbonate and brine, dried over sodium sulfate, filtered andevaporated under reduced pressure. The residue was crystallized frommethanol to give 19.9 g (71.1% yield) the compound [7a]. Analyticalprobe of the compound [7a] may be prepared by repeated crystallizationfrom mixture of hexane and ethyl acetate gave the compound [7a] with mp118-119° C. and [α]_(D) ²⁰ −91.2° (c 1, MeCN). ¹H NMR (CDCl₃) δ: 7.96(d, J=8 Hz, 2H); 7.50-7.56 (m, 4H); 7.29-7.40 (m, 3H); 7.01-7.17 (m,5H); 5.38-5.61 (m, 2H); 5.15-5.18 (m, 1H); 4.95-5.00 (m, 1H); 4.42-4.53(m, 1H); 3.95-4.05 (m, 1H); 3.55-3.80 (m, 1H); 3.15-3.40 (m, 1H). ¹³C(CDCl₃) δ: 19.4; 19.6; 25.3; 25.4; 30.7; 30.8; 31.2; 31.8; 34.5; 34.8;36.3; 37.2; 37.4; 37.6; 42.4; 42.5; 53.8; 62.3; 62.4; 74.8; 78.6; 79.0;82.8; 83.2; 94.9; 98.0; 125.7; 127.0; 127.1; 128.0; 128.1; 128.2; 128.6;128.8; 130.0; 131.3; 133.7; 134.6; 139.8; 141.7; 145.9; 146.0; 165.7;176.0; 176.2. IR (KBr): 2933; 1762; 1716; 1670; 1640; 1268 cm⁻¹.

[0058] The mother liquor which contains a mixture of the compounds [7a]and [8a] was evaporated under reduced pressure and subjected separationby column chromatography on Silica gel (elution with ethylacetate/hexane 1:2 v/v) to afford additional 2.0 g (8.4%) of compound[7a] and 0.9 g (3.8%) of isomer [8a] with mp 116-118° C. and [α]_(D) ²⁰−84.3° (c 1, MeCN). ¹H NMR (CDCl₃) δ: 7.06-8.04 (m, 14H); 5.40-5.67 (m,2H); 5.22-5.39 (m, 1H); 5.00-5.15 (m, 1H); 4.61 (m, 1H); 4.02-4.17 (m,1H); 3.78-3.87 (m, 1H); 3.30-3.50 (m, 1H); 2.45-2.93 (m, 7H); 2.18-2.28(m, 1H); 1.53-2.03 (m, 8H).

3) Preparation of(3aR,4R,5R,6aS)-hexahydro-4-[(3R)-3-hydroxy-5-phenyl-1E-pentenyl]-5-(p-phenylbenzoyloxy)-2H-cyclopenta[b]furan-2-one[6a]

[0059] Pyridinium p-toluenesulfonate (20 mg) was added to a stirredsolution of the compound [8a] (0.44 g), obtained in previous step, inmethanol (20 mL) at room temperature. The mixture was stirred at 40-50°C. for 3-4 hours (TLC monitoring) and evaporated under reduced pressure.The residue was diluted with dichloromethane (30 mL). The solution waswashed with saturated aqueous solution of sodium bicarbonate (10 mL) andbrine(10 mL), dried over sodium sulfate, filtered and evaporated to give0.35 g (93.4%) of oily residue. The residue was crystallized from amixture of hexane and ether to give compound [6a] as white crystals withmp 81-83° C. and [α]_(D) ²⁰ −124.5° (c 1, MeCN). ¹H NMR (CDCl₃) δ:7.08-8.05 (m, 14H); 5.51-5.74 (m, 2H); 5.21-5.30 (m, 1H); 5.02-5.07 (m,1H); 4.09-4.13 (m, 1H); 2.46-2.92 (m, 7H); 2.18-2.28 (m, 1H); 1.66-1.86(m, 3H). ¹³C (CDCl₃) δ: 31.6; 34.8; 37.6; 38.7; 42.7; 54.1; 71.6; 79.0;83.1; 125.9; 127.1; 127.2; 128.2; 128.3; 128.8; 128.9; 130.1; 136.2;139.9; 141.5; 146.1; 165.9; 176.2.

4) Preparation of(3aR,4R,5R,6aS)-hexahydro-4-[(3S)-3-hydroxy-5-phenyl-1E-pentenyl]-5-(p-phenylbenzoyloxy)-2H-cyclopenta[b]furan-2-one[5a]

[0060] Pyridinium p-toluenesulfonate (50 mg) was added to a stirredsolution of the compound [7a] (1.00 g) in methanol (50 mL) at roomtemperature. The mixture was stirred at 40-50° C. for 3-4 hours (TLCmonitoring) and evaporated under reduced pressure. The residue wasdiluted with dichloromethane (75 mL). The solution was washed withsaturated aqueous solution of sodium bicarbonate (25 mL) and brine(25mL), dried over sodium sulfate, filtered and evaporated to give 0.69 g(81.0%) of oily residue. The residue was crystallized from a mixture ofethyl acetate and isopropyl ether to give compound [5a] as whitecrystals with mp 126-128° C. ¹H NMR (CDCl₃) is in agreement with thestructure.

4) Regeneration of(3aR,4R,5R,6aS)-hexahydro-4-(3-oxo-5-phenyl-1E-pentenyl)-5-(p-phenyl-benzoyloxy)-2H-cyclopenta[b]furan-2-one[4a] 4.1) From Compound [6a]

[0061] A solution of pyridine sulfur trioxide (0.32 g) in DMSO (3.5 mL)was added dropwise to a stirred solution of compound [6a] (0.30 g) andtriethylamine (0.40 g) in dichloromethane (4 mL) at −5-0° C. The mixturewas stirred at the same temperature for 1 hour (TLC monitoring) andpoured into cold water (15 mL). The mixture was stirred for 10 min at0-5° C. The organic layer was separated, the water layer was extractedwith dichloromethane (3×5 mL). The combined organic layers were washedwith brine (3×10 mL), dried over sodium sulfate, filtered and evaporatedunder reduced pressure. A solution of the residue in methanol (1 mL) wascold to −10° C. and kept at the same temperature for 3 hours. Theprecipitated crystals were filtered, washed on filter with cold methanol(2×1 mL) and dried under reduced pressure to a constant weight to give0.26 g (87% yield) of crystalline compound [4a] with 94% purity by HPLC.

4.2) From Compound [5a]

[0062] A solution of pyridine sulfur trioxide (0.60 g) in DMSO (7.0 mL)was added dropwise to a stirred solution of compound [5a] (0.60 g) andtriethylamine (0.80 g) in dichloromethane (8 mL) at −5-0° C. The mixturewas stirred at the same temperature for 1 hour (TLC monitoring) andpoured into cold water (30 mL). The mixture was stirred for 10 min at0-5° C. The organic layer was separated, the water layer was extractedwith dichloromethane (3×10 mL). The combined organic layers were washedwith brine (3×20 mL), dried over sodium sulfate, filtered and evaporatedunder reduced pressure. A solution of the residue in methanol (2 mL) wascold to −10° C. and kept at the same temperature for 3 hours. Theprecipitated crystals were filtered, washed on filter with cold methanol(2×2 mL) and dried under reduced pressure to a constant weight to give0.50 g (83.7% yield) of crystalline compound [4a].

EXAMPLE 3(3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-one[9a]

[0063]

[0064] A mixture of a compound [7a] (80.0 g), palladium on carboncatalyst (16 g) and ethyl acetate (1.0 L) was stirred under hydrogenatmosphere at 150 psi for 3 hours at room temperature. The reactionmixture was then filtered and evaporated under reduced pressure. Theoily residue was crystallized from a mixture of hexane and ethyl acetate4:1 v/v to give 71.4 g (89% yield) of compound [9a], mp 103-105° C.,[α]_(D) ²⁰ −107° (c 1.0, MeCN). ¹H NMR (CDCl₃) δ: 8.03 (d, J=8 Hz, 2H);7.60-7.67 (m, 4H); 7.36-7.48 (m, 3H); 7.14-7.24 (m, 5H); 5.20-5.30 (m,1H); 5.00-5.15 (m, 1H); 4.50-4.70 (m, 1H), 3.89-3.95 (m, 1H); 3.66-3.72(m, 1H); 3.45-3.50 (m, 1H). ¹³C NMR (CDCl₃) δ: 20.1; 25.4; 28.7; 31.3;31.9; 36.5; 43.5; 52.8; 63.0; 76.0; 80.1; 84.3; 97.8; 125.7; 127.1;127.2; 128.1; 128.3; 128.4; 128.9; 130.1; 140.0; 142.4; 146.0; 165.8;176.7. IR (KBr): 2990; 1771; 1707; 1608; 1277; 1181; 1110; 1026; 751;698 cm⁻¹.

EXAMPLE 4(3aR,4R,5R,6aS)-3-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3S-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-one[22]

[0065]

[0066] A mixture of a compound [8a] (1.4 g), palladium on carboncatalyst (0.56 g) and ethyl acetate (40 mL) was stirred under hydrogenatmosphere at 40 psi for 3 hours at room temperature. The reactionmixture was then filtered and evaporated under reduced pressure. Theoily residue was purified by column chromatography on silica gel elutionwith mixture of hexane and ethyl acetate 2:1 v/v to give 1.2 g (86%yield) of compound [22] as oil, [α]_(D) ²⁰ −52.30 (c 1.0, MeCN). ¹H NMR(CDCl₃) δ: 1.41-1.86 (m, 12H); 2.00-2.25 (m, 1H); 2.34-3.00 (m, 7H);3.40-3.60 (m, 1H); 3.60-3.80 (m, 1H); 3.80-4.00 (m, 1H); 5.00-5.15 (m,1H); 4.50-4.70 (m, 1H); 3.89-3.95 (m, 1H); 3.66-3.72 (m, 1H); 3.45-3.50(m, 1H).

EXAMPLE 5(3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-one[9a]

[0067]

[0068] Pyridinium p-toluenesulfonate (20 mg) was added to a stirredsolution of compound [21a] (2.4 g) and 3,4-Dihydro-2H-pyran (1.6 g) indichloromethane (25 mL) at room temperature. The mixture was stirredovernight at room temperature (TLC monitoring), washed with saturatedaqueous solution of sodium bicarbonate and brine, dried over sodiumsulfate, filtered and evaporated under reduced pressure. The residue wascrystallized from ether and recrystallized from mixture of hexane andethyl acetate to give 2.31 g (82% yield) the compound [9a], mp 103-105°C. ¹H NMR (CDCl₃) agrees with the structure

EXAMPLE 6(3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-ol[10a]

[0069]

[0070] A 1.5 M solution of diisobutylaluminum hydride in toluene (6.0mL, 9.0 mmol) was added dropwise to a stirred solution of compound [9a](4.1 g, 7.2 mmol) in toluene (60 mL) at −70-−80° C. (acetone/dry icebath) and the resulting mixture was stirred during 1 h at the sametemperature. Methanol (10 mL) was added dropwise to the stirred mixtureat −70-−80° C. The mixture was stirred for 1 hour at room temperature,filtered and evaporated under reduced pressure. Dichloromethane (30 mL)was added to the residue. The resulting solution was washed with brine(2×10 mL), dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate 2:1 v/v) to obtain 2.0 g (49% yield) ofthe compound [10a]. ¹H NMR (CDCl₃) δ: 6.4-6.5 (m, 1H); 5.0-5.2 (m, 1H);4.7-4.9 (m, 1H); 4.5-4.7 (m, 1H); 3.8-4.0 (m, 1H); 3.6-3.8 (m, 1H);3.4-3.6 (m, 1H). ¹³C NMR (CDCl₃) δ: 20.1; 25.5; 28.6; 31.3; 31.6; 36.7;37.7; 40.3; 41.1; 46.2; 51.6; 63.0; 81.3; 82.0; 97.8; 100.2; 125.6;127.1; 127.2; 128.1; 128.3; 128.4; 128.9; 129.2; 130.0; 130.1; 140.0;145.7; 166.0. IR (KBr): 3500, 2945, 1712, 1605, 1278, 1117, 1026, 752cm⁻¹.

EXAMPLE 7(3a,4R,5R,6aS)-Hexahydro-5-hydroxy-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-ol[11a]

[0071]

[0072] A mixture of compound [10a] (2.0 g) and potassium carbonate (1.0g) in methanol (10 mL) was stirred at 40-45° C. for 5 hours (TLCmonitoring). Dichloromethane (20 mL) and water (20 mL) were added to thestirred mixture at room temperature. Organic layer was separated, washedwith water, dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel. The compound [11a] (1.0 g, 73% yield) was prepared.

EXAMPLE 8(3aR,4R,5R,6aS)-Hexahydro-5-hydroxy-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-ol[11a]

[0073]

[0074] A 1.5 M solution of Diisobutylaluminum hydride in toluene (46.0g, 69 mmol) was added dropwise to a stirred solution of compound [9a](17.0 g, 30 mmol) in toluene (500 mL) at −20-−10° C. The mixture wasstirred for 1 hour at the same temperature. Methanol (200 mL) was addeddropwise to the stirred mixture at −20-−10° C. The obtained mixture wasstirred for 1 hour at room temperature, filtered and evaporated underreduced pressure. Dichloromethane (250 mL) was added to the residue. Theresulting solution was washed with brine (2×220 mL), dried over sodiumsulfate, filtered and evaporated under reduced pressure. To completehydrolysis of p-phenylbenzoate-groups a mixture of the residue andpotassium carbonate (10:0 g) in methanol (100 mL) was stirred at roomtemperature for 7 hours (TLC monitoring). The mixture was evaporatedunder reduced pressure. A mixture of the residue, dichloromethane (300mL) and water (300 mL) was stirred for 10 min at room temperature. Theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel exane/ethyl acetate 1:2v/v) to obtain 10.3 g of the compound [11a] (88% yield), [α]_(D) ²⁰−53.5° (c 1.0, MeCN). ¹H NMR (CDCl₃) δ: 7.10-7.29 (m, 5H); 5.47-5.63 (m,1H); 4.57-4.69 (m, 2H); 3.69-3.94 (m, 2H); 3.60-3.75 (m, 1H); 3.40-3.55(m, 1H). ¹³C NMR (CDCl₃) δ: 19.9; 25.4; 29.0; 31.2; 31.9; 36.6; 40.2;41.5; 42.5; 46.4; 48.0; 55.3; 55.6; 62.8; 79.4; 79.9; 82.4; 86.4; 97.6;100.0; 101.1; 125.6; 128.2; 128.3; 142.5. IR (neat): 3398, 2944, 2867,1451 cm⁻¹.

EXAMPLE 9(3aR,4R,5R,6aS)-Hexahydro-5-hydroxy-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-ol[11a]

[0075]

[0076] A 1.5 M solution of Diisobutylaluminum hydride in toluene (12.6mL, 18.9 mmol) was added dropwise to a stirred solution of a compound[9a] (4.1 g, 7.2 mmol) in toluene (60 mL) at −70-−80° C. (acetone/dryice bath). The mixture was stirred for 1 hour at the same temperature.Methanol (50 mL) was added dropwise to the stirred mixture at −70-−80°C. and the cooling bath was removed. The mixture was stirred for 1 hoursat room temperature, filtered and evaporated under reduced pressure. Asolution of the residue in dichloromethane (150 mL) was washed withbrine (2×10 mL), dried over sodium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate 1:2 v/v) to obtaincompound [11a] (2.53 g, 90% yield).

EXAMPLE 10(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]cyclopentaneethanol[12a]

[0077]

[0078] A 1.5 M solution of diisobutylaluminum hydride in toluene (12.6mL, 18.9 mmol) was added dropwise to a stirred solution of a compound[9a] (2.0 g, 3.5 mmol) in toluene (60 mL) at room temperature. Themixture was stirred for 3 hour at the same temperature. Methanol (50 mL)was added dropwise to the stirred mixture at −5-+5° C. and the coolingbath was removed. The mixture was stirred for 1 hours at roomtemperature, filtered and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel (hexane/ethylacetate 1:5 v/v) to obtain 1.0 g (73% yield) of the compound [12a]. ¹Hand ¹³C NMR are in agreement with the structure.

EXAMPLE 11(3aR,4R,5R,6aS)-Hexahydro-5-hydroxy-4-[(3R)-5-phenyl-3-hydroxypentyl]-2H-cyclopenta[b]furan-2-ol[11b]

[0079]

[0080] A mixture of compound [11a] (0.55 g), acetic acid (2 ml), THF (2mL) and water (2 mL) was stirred at 40-50° C. for 4 hours (TLCmonitoring). The mixture was basified with 1 N aq. potassium hydroxideto pH 10-11 and the product was extracted with dichloromethane (3×20mL). The combined organic layers were dried over sodium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel (elution with gradient ethylacetate/hexane from 1:2 to 3:1 v/v) to give 0.18 g (43%) of the compound[11b] as a colorless oil. ¹H NMR (CD₃OD) is compatible with literaturedata.

EXAMPLE 127-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]cyclopentyl]-5Z-heptenoicacid [13a]

[0081]

[0082] Potassium tert-butoxide (33.3 g) was added to a stirredsuspension of (4-carboxybutyl)triphenylphosphonium bromide (66.0 g) inTHF (200 mL) at 0-5° C. and the mixture was stirred at room temperatureduring 0.5 h. A solution of compound [11a] (13.0 g) in THF (100 mL) wasadded dropwise during 2 hours to the resultant red orange suspension ofpotassium 5-(triphenylphosphoranylidene)pentanoate at −15° C. Themixture was stirred for 3 hours at this temperature (TLC monitoring) andpoured into ice water (1 L). The alkaline solution was washed witht-BuOMe (4×500 mL), mixed with ether (500 mL) and acidified with 10%aqueous solution of citric acid to pH 4. The white precipitated crystalswere filtered off and washed on filter with ether (200 mL). The etherlayer was separated from combined filtrates. The water phase wasextracted with ether (200 mL). The combined organic extracts wereconcentrated to a volume 400 mL, washed with water (5×200 mL), driedover sodium sulfate, filtered and evaporated under reduced pressure togive 13.5 g (86% yield) of the compound [13a].

EXAMPLE 13

[0083]

[0084] Pyridinium p-toluenesulfonate (70 mg) was added to a stirredsolution of the compound [13a] (1.8 g) in methanol (50 mL) at roomtemperature. The mixture was stirred at 50° C. over a period of 4 h, bywhich time the reaction was complete (HPLC monitoring). The mixture wasevaporated under reduced pressure. Water (10 mL) and ethanol (10 mL)were added to a residue. The mixture was basified with 1 N aq. NaOH topH 12, stirred for 1 hour at 70-75° C. and evaporated under reducedpressure. A solution of the residue in water (50 mL) was extracted withethyl acetate (5×20 mL), acidified with 10% aq. citric acid to pH 4 andextracted with ether (3×50 mL). The combined organic extracts were driedover sodium sulfate, filtered and evaporated under reduced pressure togive 1.35 g (96% yield) of compound [13b] as colorless oil. The compound[13b] may be purified by chromatography on silica gel (elution withhexane/ethyl acetate 1:1 v/v) or by crystallization its salts withtromethamine, histamine, L-arginine, triptamine or adamantanamine fromvarious solvents following isolation of the purified compound [13b] fromthe salts.

EXAMPLE 147-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]cyclopentyl]-5Z-heptenoicacid, isopropyl ester [17a]

[0085]

[0086] 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.73 g) was added dropwise toa stirred solution of compound [13a] (1.66 g) in acetone (15 mL) at 0°C. The solution was warmed to room temperature, and isopropyl iodide(3.6 g) was added dropwise to it. The resulting mixture was stirredovernight at room temperature (TLC monitoring). The mixture wasconcentrated to a volume 5 mL, dichloromethane (70 mL) was added and theresulting mixture was washed with 3% aqueous solution of citric acid(2×20 mL), 5% aqueous solution of sodium bicarbonate (2×10 mL) andbrine, dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue (1.8 g) was purified by column chromatography onsilica gel (eluent hexane/ethyl acetate 2:1 v/v) to obtain 1.3 g (72%yield) of the compound [17a]. ¹H NMR (CDCl₃) δ: 7.14-7.29 (m, 5H);5.27-5.46 (m, 2H); 4.91-5.03 (mn, 1H); 4.58-4.64 (m, 1H); 4.07-4.13 (m,1H); 3.71-3.92 (m, 2H); 3.66-3.71 (m, 1H); 3.45-3.50 (m, 1H); 1.19 (d,J=8 Hz, 6H). ¹³C NMR (CDCl₃) δ: 20.0; 20.4; 21.8; 25.0; 25.5; 26.7;27.1; 29.1; 31.3; 32.0; 34.1; 36.7; 42.5; 51.8; 53.3; 62.9; 67.5; 74.8;78.9; 97.8; 125.6; 125.8; 128.3; 128.4; 129.3; 129.5; 129.6; 143.0;173.3.

EXAMPLE 15

[0087]

[0088] Pyridinium p-toluenesulfonate (16 mg) was added to a stirredsolution of the compound [17a] (0.7 g) in ethanol (20 mL) at roomtemperature. The mixture was stirred at 50° C. over a period of 3 hours,by which time the reaction was complete (TLC monitoring). The mixturewas concentrated under reduced pressure. The residue was diluted withdichloromethane (40 mL). The solution was washed with water (10 mL) andbrine (10 mL), dried over sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate 1:1 v/v) to obtain Latanoprost. ¹H NMR (CDCl₃)is compatible with literature data.

EXAMPLE 16

[0089]

[0090] A mixture of Latanoprost acid [13b] (0.95 g, 2.4 mmol), isopropyliodide (0.83 g, 4.8 mmol), cesium carbonate (1.20 g, 3.6 mmol) and DMF(20 mL) was stirred for 2-3 hours at 40-50° C. (TMC monitoring) andpoured into a stirred mixture of 2 M aqueous NaHSO₄ (2.5 mL, 5 mmol),ice (50 mL) and ether (50 mL). The organic layer was separated and thewater phase was extracted with ether (2×50 mL). The combined organiclayers were washed with brine (50 mL), dried over sodium sulfate,filtered and evaporated under reduced pressure to give 1.05 g (100%yield) of crude product. The crude product was purified by columnchromatography on silica gel (hexane/ethyl acetate 1:1 v/v) to giveLatanoprost. ¹H NMR (CDCl₃) is compatible with literature data.

[0091] Although certain presently preferred embodiments of the inventionhave been described herein, it will be apparent to those skilled in theart to which the invention pertains that variations and modifications ofthe described embodiments may be made without departing from the spiritand scope of the invention. Accordingly, it is intended that theinvention be limited only to the extent required by the appended claimsand the applicable rules of law.

1. A process for the preparation of Latanoprost [1]

which comprises deriving the compound [5]

to give the compound [7]

which is hydrogenated in the presence of catalyst to give the compoundof the Formula [9]

which is reduced with diisobutylaluminum hydride at temperature rangefrom −50 to +50° C. followed by hydrolysis of the obtained reactionmixture under basic conditions to give compound [11], which is convertedinto latanoprost [1]

werein one of R¹ and R² is an aryl carbonyl and the other one isselected from the group consisting of aryl carbonyl, acyl,trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted andalkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-ylgroups, and R³ is hydrogen when R¹ is acyl and is equal to R¹ when it istrialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted oralkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-ylgroups; R⁴ is hydrogen when R² is acyl and is equal to R² when it istrialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted oralkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-ylgroups.
 2. A process according to claim 1 wherein the said reduction ofthe compound [9] with diisobutylaluminum hydride is provided attemperature range from −20 to +20° C.
 3. A process according to claim 1wherein the said catalyst contains palladium, platinum or nickel.
 4. Aprocess according to claim 1 wherein the said catalyst is palladium oncarbon.
 5. A process according to claim 1 wherein the said hydrogenationof the compound [7] is carried out in the presence of bases and/orsalts.
 6. The process defined in claim 1, which comprises isolating thecompounds of Formulae [7] and [9] in the course of the synthesis and, ifdesired, purifying them by re-crystallization.
 7. Compound of theformula [7]:

werein one of R¹ and R² is an aryl carbonyl group and the other one isselected from the group consisting of aryl carbonyl, acyl,trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted andalkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-ylgroups.
 8. Compound of the formula [9]:

werein one of R¹ and R² is an aryl carbonyl group and the other one isselected from the group consisting of aryl carbonyl, acyl,trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted andalkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-ylgroups.
 9. Compound of the formula [11]:

werein R³ and R⁴ are selected from the group consisting of hydrogen,trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted andalkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-ylgroups, and one of the R³ and R⁴ is hydrogen group. 10.(3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3S)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]-1E-pentenyl]-2H-cyclopenta[b]furan-2-one[7a]:

wherein PPB is p-phenylbenzoyl group and THP is tetrahydro-2H-pyran-2-ylgroup. 11.(3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-one[9a]:

wherein PPB is p-phenylbenzoyl group and THP is tetrahydro-2H-pyran-2-ylgroup. 12.(3aR,4R,5R,6aS)-Hexahydro-5-hydroxy-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-ol[11a]:

wherein THP is tetrahydro-2H-pyran-2-yl group.
 13. A process accordingto claim 1 wherein R¹ and R² are selected from the group consisting ofbenzoyl, p-toluoyl, p-phenylbenzoyl and tetrahydro-2H-pyran-2-yl groups,and at least one of the R¹ and R² is arylcarbonyl group.
 14. A processaccording to claim 1, wherein compound [11] is converted intolatanoprost [1] by reacting [11] with a metal salt of5-(triphenylphosphoranylidene)pentanoic acid to form a compound offormula [13]

wherein R³ and R⁴ are as defined above; and when R³ and/or R⁴ incompound [13] is other than hydrogen, removing the protecting group toyield latanoprost acid [13b]

following esterifycation of compound [13b] with compound [16]: (CH₃)₂CHXwherein X is a leaving group, in the presence of a base to obtainlatanoprost [1].
 15. A process according to claim 14, wherein said baseis cesium carbonate.